Heteromerization of dopaminergic receptors in the brain: Pharmacological implications.

Dopamine exerts its physiological effects through two subtypes of receptors, i.e. the receptors of the D1 family (D1R and D5R) and the D2 family (D2R, D3R, and D4R), which differ in their pattern of distribution, affinity, and signaling. The D1-like subfamily (D1R and D5R) are coupled to Gαs/olf proteins to activate adenylyl cyclase whereas the D2-like receptors are coupled to Gαi/o subunits and suppress the activity of adenylyl cyclase. Dopamine receptors are capable of forming homodimers, heterodimers, and higher-order oligomeric complexes, resulting in a change in the individual protomers' recognition, signaling, and pharmacology. Heteromerization has the potential to modify the canonical pharmacological features of individual monomeric units such as ligand affinity, activation, signaling, and cellular trafficking through allosteric interactions, reviving the field and introducing a new pharmacological target. Since heteromers are expressed and formed in a tissue-specific manner, they could provide the framework to design selective and effective drug candidates, such as brain-penetrant heterobivalent drugs and interfering peptides, with limited side effects. Therefore, heteromerization could be a promising area of pharmacology research, as it could contribute to the development of novel pharmacological interventions for dopamine dysregulated brain disorders such as addiction, schizophrenia, cognition, Parkinson's disease, and other motor-related disorders. This review is articulated based on the three criteria established by the International Union of Basic and Clinical Pharmacology for GPCR heterodimers (IUPHAR): evidence of co-localization and physical interactions in native or primary tissue, presence of a new physiological and functional property than the individual protomers, and loss of interaction and functional fingerprints upon heterodimer disruption.

Assessment of Drug Use Pattern Using WHO Core Prescribing Indicators at Outpatient Settings of Governmental Hospitals in Dessie Town.

BACKGROUND: Enhancing the standards of medical treatment at all levels of the healthcare delivery system can improve the quality of life in developing countries. One method to promote rational drug use is an assessment of drug use pattern based on drug use indicators. OBJECTIVE: To evaluate prescription patterns at the outpatient pharmacy of Dessie Referral Hospital and Boru Meda Hospital at Dessie town. METHODS: An institution-based retrospective cross-sectional study was conducted to assess the prescribing patterns in governmental hospitals of Dessie town from April 1 to May 30, 2019. Six hundred eligible prescriptions were selected from each hospital through a systematic random sampling technique. RESULTS: The result of this study showed that both hospitals used standard prescriptions (100%). Age (99.0%) and name (94.7%) of patients were the most commonly recorded patient information while weight, address of patients and diagnosis were recorded only in 1.1%, 39.2% and 61.3% of the studied prescription papers, respectively. A total 2409 drugs were prescribed in the 1200 prescription papers and the percentage of encounters with injection(s) and antibacterial(s) was 9.0% and 42.6%, respectively. At each hospital, all drugs were prescribed from the Ethiopian essential drug list. CONCLUSION: The present study revealed the use of standard presecription papers at both hospitals. None of the patient-related information was completely written in all prescrptions. For drug-related information, only the name of the drug was written in all prescription papers. There is also a significant deviation from the acceptable WHO standard for prescribing antibiotics.

Evaluation of Antibiotic Utilization Pattern During Acute Diarrheal Disease at Chefa-Robit Health Center, Kemissie, North East Amhara, Ethiopia.

BACKGROUND: Despite the fact that the majority of the acute diarrheal diseases are viral in origin and self-limited, routine and injudicious antibiotic treatment is a common practice globally and more prevalent in Africa. Indeed, the irrational use of antibiotics has a detrimental effect on the issue of antibiotics resistance and associated healthcare costs. Accordingly, a health center-based cross-sectional study is mandatory and was conducted due to the common malpractice of antibiotics use. OBJECTIVE: The aim of this study was to evaluate the antibiotic use pattern in the treatment of acute diarrheal disease in Chefa-robit health center, Kemissie, Northeastern Ethiopia. METHODS AND MATERIALS: A retrospective cross-sectional study was conducted to evaluate the antibiotic utilization pattern for the treatment of acute diarrheal disease. Data was collected from 230 patients' record cards treated for acute diarrheal disease from January 2018 to December 2018 using structured questionnaires. The finding is presented using frequency distribution and percentages in tables as well as figures. RESULTS: Among the 230 patients, 49.60% were males and the rest were females. From the total, 172 of them were with watery type of diarrhea and 132 of them were prescribed antibiotics inappropriately out of which 77 were under 5 years. In addition, 27 patients were diagnosed with mucoid diarrhea and only eight of them were treated with antibiotics whereas 31 patients were with bloody type of diarrhea and 10 of them were not treated with antibiotics. Of the 230 cases, 161 (70%) patients received different types of antibiotics, and co-trimoxazole, amoxicillin and ciprofloxacin were the most prescribed antibiotics. CONCLUSION: The study revealed that there is a high level of inappropriate antibiotics use which may fuel the increased antimicrobial resistance and associated costs nationally as well as globally.

Chemo Suppressive and Curative Potential of Hypoestes forskalei Against Plasmodium berghei: Evidence for in vivo Antimalarial Activity.

BACKGROUND: The emergence of drug resistance together with the global burden of malaria triggers the necessity for the searching of new antimalarial agents. This study, therefore, was initiated to investigate the in vivo antimalarial activity of Hypoestes forskalei in mice based on the strong supported evidence from the ethnobotanical claims and the in vitro anti-plasmodial activity of the plant. METHODS: The 4-day suppressive (crude extract and fractions) and the Rane's (n-butanol fraction) tests were used to evaluate the antimalarial activity of the plant. A cold maceration technique with 80% methanol was used for the crude extraction of the plant. The crude extract was then fractionated using solvents of different polarity (chloroform, n-butanol, and water). RESULTS: All the test doses of the crude extract as well as the fractions reduced parasitemia and prolonged mean survival time significantly (P<0.001) as compared to their negative control groups. Maximum parasitemia suppression effect (56%) was observed at the highest dose (600 mg/kg) of the crude extract during the 4-day suppressive test. Likewise, the n-butanol, chloroform, and aqueous fractions showed a percentage suppression of about 50, 38, and 19, respectively, at the dose of 600 mg/kg. Therefore, the n-butanol fraction showed the highest parasitemia suppression followed by the chloroform fraction and then the aqueous fraction. Moreover, the n-butanol fraction showed a significant curative effect (P<0.001) in Rane's test with a percentage suppression of about 49 at a dose of 600 mg/kg. CONCLUSION: The study has revealed that the plant has a promising antimalarial activity, the activity being more in the crude extract than the fractions. The highest antimalarial activity of the n-butanol fraction suggests that non-polar and medium polar principles could be responsible for the observed activity.

Surgical Antibiotic Prophylaxis Use and Surgical Site Infection Pattern in Dessie Referral Hospital, Dessie, Northeast of Ethiopia.

BACKGROUND: Surgical site infections are the third (14%-16%) most frequent cause of nosocomial infections among hospitalized patients. They still form a large health problem and result in increased antibiotic usage, increased associated costs, and prolonged hospitalization and contribute to increased patient morbidity and mortality. Therefore, studies on surgical site infections and surgical antibiotic prophylaxis contribute to identifying surgical site infection rate and risk factor associated with it as well as for identifying the gap in surgical antibiotic prophylaxis practice. OBJECTIVE: To assess surgical antibiotic prophylaxis practice and surgical site infection among surgical patients. METHOD: A hospital-based prospective observational study was conducted in 68 patients who underwent major surgery in Dessie Referral Hospital adult surgical wards between March 24 and April 25/2017. Descriptive and logistic regression analyses were performed to determine infection rate and risk factors for surgical site infections. RESULT: Assessment of 68 patients who underwent major surgery revealed an overall surgical site infection rate of 23.4%. Prophylactic antibiotics were administered for 59 operations; of these, 33 (48.6%) had inappropriate timing of administration. A combination of ceftriaxone and metronidazole 28 (47.46%) was frequently used. Factors associated with surgical site infection were wound class, patient comorbid condition, duration of the procedure, the timing of administration, and omitting prophylaxis use. CONCLUSION: This study indicated a higher rate of surgical site infection and also revealed that wound class, preexisting medical condition, prolonged duration of surgery, omitting of prophylaxis use, and inappropriate timing of administration were highly associated with surgical site infection.

Wound Healing Effect of Acokanthera schimperi Schweinf (Apocynaceae) Methanol Leaf Extract Ointment in Mice and Its in-vitro Antioxidant Activity.

BACKGROUND: Acokanthera schimperi is traditionally used for the treatment of wounds and various bacterial infections. Due to the ongoing escalation of antimicrobial resistance, there is an increasing demand for the appropriate wound care and hence, the present study was initiated to investigate the wound healing effects of the leaf extract ointments of A. schimperi in mice and its in-vitro antioxidant activity. METHODS: The crude extract was prepared as 5% and 10% w/w ointments for topical use in mice. Wound contraction and epithelialization period were determined in excision and infected models, whereas tensile strength was determined in an incision model. Besides, its antioxidant activity was evaluated using the DPPH method. RESULTS: In this study, the 10% w/w extract ointment did not cause toxicity at the 2000 mg/kg limit dose. In the excision model, the 10% w/w ointment exhibited a significant wound contraction effect starting from day 6 to 14 with a complete epithelization shown on day 13. Besides, the 5%w/w ointment showed a significant wound contraction effect starting from day 6 onwards, and a significant decrease in the epithelization period observed on day 16. Conversely, both the 10% w/w and 5% w/w ointments showed significant wound contraction effects starting from day 4 and onwards in the infected model. However, a complete epithelization period was observed on days 14 and 18 in the 10%w/w and 5% w/w/extract ointment treated groups, respectively. In the incision model, the 10% (w/w) and 5% (w/w) extract ointments showed a significant increase in tensile strength by 36.80 and 32.23%, respectively. Moreover, the antioxidant activity of the extract was concentration-dependent with an IC50 value of 5.49± 0.38 µg/µL. CONCLUSION: The potential wound healing effects of this plant may provide a candidate source in the discovery of new drugs for the treatment of wounds.

Antimalarial Activity of Fagaropsis angolensis (Rutaceae) Crude Extracts and Solvent Fractions of Its Stem Bark Against Plasmodium berghei in Mice.

BACKGROUND: A current challenge in malaria control and elimination is the progressive resistance to most antimalarial drugs which necessitates the discovery of new options. Hence, the current study was initiated to investigate the antimalarial activity of the stem bark of Fagaropsis angolensis in mice. METHODS: The test material was extracted using 80% methanol in a cold maceration technique and further fractionated in solvents of varied polarity. Acute oral toxicity was assessed following the OECD guideline no. 425 protocol. Then, the antimalarial activities of the crude extract and the fractions were evaluated in a 4-day suppression test. Rane's test was also used to evaluate the curative potential of the n-butanol fraction that showed the highest effect during the 4-day suppressive test. Parameters such as parasitemia suppression, mean survival time, packed cell volume, rectal temperature, and body weight were determined to establish the activity. RESULTS: The acute oral toxicity test indicated that the plant did not cause any signs of behavioral changes or mortality at 200 mg/kg limit dose. In a 4-day suppression test, a significant dose-dependent reduction in the parasitemia level and prolongation of survival time were observed (p<0.001) in all three doses of the crude extract compared with the negative control. The crude extract also exhibited a significant (p<0.001) protective effect in packed cell volume and rectal temperature decline in all three doses in a dose-dependent fashion compared with the negative control. Among all fractions, the n-butanol fraction displayed the highest effects in all parameters in the 4-day suppression test. In addition, the n-butanol fraction also showed a significant percentage of parasitemia suppression effects at all doses in Rane's test. Furthermore, higher free radical scavenging activity was observed in the n-butanol fraction and the 80% methanol extract. CONCLUSION: This study established that Fagaropsis angolensis had shown potential antimalarial activity as evidenced by the significant effects in the different parameters, upholding its traditional use for the treatment of malaria and laying the foundation for further investigations.

Evaluation of the anti-malarial activity of crude extract and solvent fractions of the leaves of Olea europaea (Oleaceae) in mice.

BACKGROUND: Drug resistance poses a challenge to malaria control measures. This calls for discovery & development of new chemotherapeutic agents. This study therefore was initiated to investigate the antimalarial activity of Olea europaea against Plasmodium berghei infected mice and to further ascertain in which fraction (s) the constituents responsible for anti-malarial activity are concentrated. METHODS: The leaves of Olea europaea were extracted by maceration using 80% methanol and the crude extract was then successively fractionated with solvents of differing polarity (chloroform, n-butanol and water). The anti-malarial activity of various doses of the extract and fractions (200, 400 and 600 mg/kg) was evaluated using chemo-suppressive, curative, and repository tests. Parameters, including parasitemia, rectal temperature, body weight, and packed cell volume were determined to establish the activity. RESULTS: The acute oral toxicity test result revealed that the LD50 values of the extract and fractions were greater than 2000 mg/kg in mice. The crude extract significantly reduced parasitemia (p < 0.001) and prolonged survival time (p < 0.001), in a dose-dependent manner, in all tests, as compared to the negative control group. Higher parasitemia suppression (58%) was achieved with the larger dose (600 mg/kg) in the 4-day suppressive test, suggesting that the crude extract has largely a chemo-suppressive activity. Parasitemia was significantly reduced (p < 0.001) by all fractions in all doses used when compared to the negative controls, with the rank order of n-butanol (51%) > chloroform>aqueous (21%) fractions. Larger (600 mg/kg) and middle (400 mg/kg) doses of the crude extract as well as the fractions ameliorated all the other parameters in a consistent manner, with the crude being more active than the fractions. Preliminary phytochemical analysis revealed the presence of secondary metabolites that were differentially distributed in the fractions. CONCLUSION: The findings collectively indicate that the plant is endowed with antimalarial activity, the activity being more in the crude extract than the fractions, owing to the presence of secondary metabolites that act independently or in synergy. The varying degree of antimalarial activity in the fractions suggests that non-polar and medium polar principles could be responsible for the observed activity.

Self-Reported and Actual Involvement of Community Pharmacy Professionals in the Management of Childhood Diarrhea: A Cross-Sectional and Simulated Patient Study at two Towns of Eastern Ethiopia.

BACKGROUND: Role of community pharmacy professionals is observed in the prevention and treatment of diarrhea and the associated problem of dehydration in children. The aim of this study was to assess self-reported knowledge and actual practices of community pharmacy professionals toward the management of diarrhea in Harar town and Dire Dawa city administration. METHODOLOGY: Community-based cross-sectional study was conducted on community pharmacy professionals practicing in community drug outlets of the two towns. Structured questionnaires and simulated patient were used to collect data. RESULTS: A total of 105 community pharmacy professionals from 105 community pharmacies were invited, out of which 69.5% were men. Age was the most frequently taken history in both studies and none of the participants take history about weight of the child, medication history, and nutrition condition in the simulated study. Even though more than 90% of the participants reported to recommend oral rehydration salt (ORS) plus zinc, above 85% of them dispense antimicrobial agents for the simulated patient. Dose (96%), frequency (98%), how to prepare ORS (98%), and duration (98%) were the most frequently given information in the questionnaire survey. However, the simulated study revealed that information about common side effects and major interactions were not given to the patient. CONCLUSION: The study identified that there is a great difference between self-reported knowledge and actual practices on the management of childhood diarrhea in community pharmacies.

Retrospective evaluation of cotrimoxazole use as preventive therapy in people living with HIV/AIDS in Boru Meda Hospital.

BACKGROUND: Drug use evaluation is a performance improvement method that focuses on evaluating and improving drug use process to achieve optimal patient outcomes. Drug use evaluation helps in identifying, preventing or resolving actual and potential drug related problems. The objective of the study was to evaluate the use of cotrimoxazole as preventive therapy in people living with HIV/AIDS in Boru Meda Hospital, Northeast Ethiopia. METHODS: A retrospective drug use evaluation was conducted on patients' medical history records based on a validated drug use evaluation criteria according to the national guideline. Medical history records of 248 patients were selected using systematic sampling method. RESULTS: The result showed that 49.6% of the patients were at WHO clinical stage III at the start of cotrimoxazole preventive therapy. In this study, the use of cotrimoxazole preventive therapy was consistent with the guideline in the rationale for indication (97.98%), dose (96.77%), and its use despite the presence of contraindications (91.93%). Problems regarding drug-drug interaction were identified in 49.59% of cases, and 20.97% of patients discontinued cotrimoxazole preventive therapy due to different reasons. CONCLUSIONS: In most patients cotrimoxazole preventive therapy was consistent with the national guideline regarding the rationale for indication, dose, discontinuation and its use in the presence of contraindications.