AN EVALUATION OF OBSTETRICAL ANALGESIA

Relief of pain and safety of mother and child are fundamentals in obstetrical analgesia. Elimination of those drugs which are ineffective or dangerous is the best guide to proper medication. Morphine, codeine, or similar opium derivatives should be avoided as they depress fetal respiration. Barbiturates have the same fault, despite their popularity.Demerol in small dosage is safe and effective. Scopolamine yields excellent results with safety. Magnesium sulfate potentiates and reinforces the action of scopolamine and involves no danger. This combination of drugs may be used by any competent general practitioner in the home or hospital.     

Aspects of morphine chemistry important to persons working with cold-blooded animals, especially fish

The relative amounts of the different forms of morphine, and many other pharmacologic agents, depend on temperature and pH. Some forms are more efficacious because they are uncharged and can penetrate lipid membranes more easily than the charged forms. Persons who administer pharmacologic agents to ectotherms (that is, cold-blooded animals) should consider the effect of temperature on the relative amounts of the different forms of drugs. For example, the fraction of morphine present in the uncharged form is twice as high in a fish or frog at 5 degrees C as in a mammal at 37 degrees C. Moreover, because the pH of blood, plasma, and tissues of ectotherms is higher when they are held at lower temperatures, the combined effect of temperature and pH on the speciation of pharmacologic agents also should be considered. In addition, the total solubility of morphine and other pharmacologic agents depends on temperature and pH. The purpose of this overview is to describe how temperature and pH influence the solubility and speciation of morphine.     

Role of the medium acidity in the complexes formation of pyropheophorbide a with albumin and lipoproteins

The spectral characteristics of the photosensitizer pyropheophorbide a (PPP) complexes with its carriers, that is, serum albumin and low density lipoproteins, were investigated in aqueous solutions at pH 7.4 and 5.0. The acidic pH had no effect on the quantitative parameters of PPP binding to lipoproteins but reduces its affinity for albumin. Differential role of acidification in the binding of PPP to biomacromolecules should be considered in the design of PPP-based drugs given that pH is frequently lowered in the sites of the disease.     

Role of the medium acidity in the complex formation of pyropheophorbide <Emphasis Type="Italic">a</Emphasis> with albumin and lipoproteins

The spectral characteristics of the photosensitizer pyropheophorbide a (PPP) complexes with its carriers, that is, serum albumin and low density lipoproteins, were investigated in aqueous solutions at pH 7.4 and 5.0. The acidic pH did not affect the quantitative parameters of PPP binding to lipoproteins, whereas the affinity to albumin decreased. Differential role of acidification in the binding of PPP to biomacromolecules should be considered in the design of PPP-based drugs, given that pH is frequently lowered in the sites of the disease.     

Drugs Versus Diets: Disillusions with Dutch Health Care

Biology incorporated into other disciplines is often distorted, alarmingly so in some areas of medicine. Together with other forms of bias, this may have detrimental effects for patients depending on medical research for their health. A case study concerning omeprazole (Losec), one of the acid-suppressive drugs against gastric ulcers, and NSAIDs, non-steroid anti-inflammatory drugs, confirms that distorted biology together with biased health care policies foster disasters in current biomedicine and medical practice. In our country, The Netherlands, omeprazole is presumably the most commonly used medication. NSAIDs are also used in large quantities, increasingly since they have become available as analgesic over-the-counter drugs. Unofficial and official sources tend to inform the general public that the drugs promote human health. We argue that their being used on a massive scale is actually a medical disaster. The health of many patients would be served better if the drugs they take were replaced by proper forms of diet, but the pharmaceutical industry, the most potent force affecting medication policies, appears to prevent a shift in the balance from over-medicalization towards healthy life styles. The shift should come from government agencies responsible for regulation in the medication market. Policies of these agencies are now a dismal failure.     

Increase in the sensitivity and a simplification of the method for the separate determination of antibiotic activities in combined preparations (oletetrin) by using media with a varying pH value

An agar-diffusion method for determination of oleandomycin and tetracycline low levels in solutions of the drug combination was developed. The medhod may be used for investigation of oletetrin absorption and distribution in humans and animals. It provides high accuracy in separate determination of oleandomycin and tetracycline activity in solutions of the drugs at a ratio of 1 : 2. The same test-culture, Bac. subtilis, variant L2 is used for the assay of tetracycline and oleandomycin activity. The only differences are in the values of pH and the buffer solution and the standards.     

Preparation and stabilization of aqueous/ethanolic superoxide solutions

Methods for the generation and stabilization of alkaline aqueous and/or ethanolic superoxide solutions have been developed utilizing either high energy ionizing radiation or vacuum-uv photolysis. These solutions can be used for the study of the reactivity of superoxide radical (O-2) and its conjugate acid the perhydroxyl radical (HO2) with other compounds over the entire pH range. Frozen, they can be kept at -196 degrees C for prolonged time periods with little loss in superoxide radical. As these solutions can be rendered free of molecular oxygen, studies of the reactivity of HO2/O-2 with oxygen-sensitive compounds under virtually anaerobic conditions are possible.     

Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs

Catecholamine neurotransmitters such as norepinephrine, dopamine, and related catecholamine derivatives reduce nitroheterocyclic drugs such as nitrofurantoin, nifurtimox, nifuroxime, nitrofurazone, misonidazole, and metronidazole in slightly alkaline solutions. Drugs which contain 5-nitrofurans are reduced at lower pH than drugs which contain 2- and 5-nitroimidazoles. 5-Nitroimidazole derivatives such as metronidazole and ronidazole are known to be more difficult to reduce than 2-nitroimidazole derivatives, due to their lower redox potential. Catecholamines, when reducing nitro drugs, undergo concomitant oxidation to form semiquinone radicals. Both semiquinone radicals and nitro anion radicals formed in a reaction of nitro drug and catecholamine derivative were detected by electron spin resonance spectroscopy. Oxygen consumption studies in solutions containing nitro drug and catecholamine derivative showed that nitro anion radicals formed under aerobic conditions reduce oxygen to form the superoxide radical and hydrogen peroxide. Quinones formed in the reaction of catecholamine and nitro drug were detected by optical spectroscopy. Biosynthetic precursors and some metabolic products of catecholamines were also used in these studies, and they all exhibited reactions similar to catecholamines. Bovine chromaffin granules which synthesize and store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin. These radicals formed inside the granules were observed by ESR spectroscopy. The formation of nitrofurantoin radical, semiquinone radicals of catecholamines, and oxygen-derived radicals by chromaffin granules is proposed to cause damage to adrenal medulla, and this process may lead to neurotoxicity.     

Volume and acidity of residual gastric fluid after oral fluid ingestion before elective ambulatory surgery.

We studied 211 unselected, healthy, adult patients scheduled to undergo elective ambulatory surgery to determine whether the volume or pH of gastric fluid at induction of anesthesia is correlated with the duration of the preoperative fluid fast. Patients were instructed that they must not eat any solid food after midnight but that they were permitted to drink 150 ml of tea, coffee, apple juice or water until 3 hours before their scheduled time of surgery. Patients with gastric disorders and those taking medications that affect gastric motility or secretion were excluded. No premedicant drugs were given. Following induction of general anesthesia the gastric fluid was aspirated through an orogastric tube, its volume recorded and its pH measured with a calibrated pH meter. The patients were retrospectively assigned to one of four groups according to the interval from last fluid ingestion until induction of anesthesia (less than 3 hours, 3 to 4.9 hours, 5 to 8 hours and nothing after midnight). The mean values and extremes for gastric fluid volume and pH were similar in the four groups. We conclude that healthy patients should be allowed to ingest fluid until 3 hours before elective ambulatory surgery.     

NONSURGICAL TREATMENT OF CONVERGENT STRABISMUS

It is generally agreed that surgical treatment of convergent strabismus should be withheld until all other less traumatic approaches have proved ineffectual. There are four categories of nonsurgical treatment.One is psychiatric. Too often psychiatric problems in the causation of convergent strabismus are either overlooked or unrecognized.Another is the proper employment of optical devices. For example, spectacle lenses to eliminate the need for excessive accommodation with its associated convergence excess, and the employment of prisms in the lenses to permit the two eyes to see as a unit even though they may not be properly anatomically oriented.Another kind of treatment is orthoptics, the use of exercises and rather complex optical equipment in a laboratory to train the patient in coordination between the two eyes.Treatment with drugs is based on the fact that certain drugs reduce the effort necessary for accommodation (much as eye-glasses do) and therefore lessen the stimulus toward convergence which may possibly tend toward the development of convergent strabismus.     

The Chemotherapy of Cardiac Arrest

Direct-air ventilation, external cardiac compression, and external defibrillation are established techniques for patients who unexpectedly develop cardiac arrest. The proper use of drugs can increase the incidence of successful resuscitation. Intracardiac adrenaline (epinephrine) acts as a powerful stimulant during cardiac standstill and, in addition, converts fine ventricular fibrillation to a coarser type, more responsive to electrical defibrillation. Routine use of intravenous sodium bicarbonate is recommended to combat the severe metabolic acidosis accompanying cardiac arrest. Lidocaine is particularly useful when ventricular fibrillation or ventricular tachycardia tends to recur. Analeptics are contraindicated, since they invariably increase oxygen requirements of already hypoxic cerebral tissues. The following acrostic is a useful mnemonic for recalling the details of the management of cardiac arrest in their proper order: A (Airway), B (Breathing), C (Circulation), D (Diagnosis of underlying cause), E (Epinephrine), F (Fibrillation), G (Glucose intravenously), pH (Sodium bicarbonate), I (Intensive care).     

Invertase and maltase in the free space of the maize scutellum

When maize scutellum slices were incubated in solutions of sucrose or maltose, there was a release of glucose into the bathing solution. The pH optima for glucose release were 2.5 for sucrose and 3.5 for maltose. From measurement of rates of glucose uptake into slices in the presence or absence of sucrose, it is calculated that glucose uptake will introduce errors of 3–9%, depending on the sucrose concentration, in estimates of free-space sucrose-hydrolase activity at pH 2.5. At their respective pH optima, maltose was hydrolysed at a rate 2.5 times that of sucrose. When frozen-thawed slices were used the same pH optima were obtained, but rates of hydrolysis were increased. Raffinose and melezitose also were hydrolysed with pH optima of 2.5 and 3.5, respectively. α-Methyl glucose was not hydrolysed. A 60-min HCl treatment (pH 2) of scutellum slices destroyed 69% of the sucrose-hydrolase activity and 100% of the maltose-hydrolase activity. In contrast, sucrose uptake and sucrose synthesis from exogenous fructose were not affected by HCl treatment. It is concluded that there are two hydrolases, acid invertase and maltase; that they are either on or outside the plasmalemma (in the free space); and that they are not necessary to the disaccharide uptake processes either by supplying exogenous hexose or by acting as transporters.     

In vivo veritas, in vitro artificia

Recently, the understanding of dynamic cellular changes that occur in vivo has advanced significantly, both at the extracellular and intracellular levels. These changes might fluctuate with daily, circadian, weekly, or monthly intervals, and the approaches used to understand these changing conditions in vitro should parallel in vivo studies. In addition, the in vitro milieu should be optimized and better defined, so that artifacts due to in vitro culture systems would not pose dangers for the proper interpretation of results. In this article, we discuss some of these issues and propose solutions.     

Pain relief in active patients with cancer: the early use of nerve blocks improves the quality of life.

Analgesic drugs are the first line of pain relief in cancer, but they should not be the only treatment offered. If nerve blocks and other destructive procedures are to be used they should be used early with conviction and persistence. They might not be being used because there are not enough doctors who can use them properly.     

Acidic hydrolysis of N-Ethoxybenzylimidazoles (NEBIs): potential applications as pH-sensitive linkers for drug delivery

This paper describes the development of a new class of N-linked imidazoles as potential pH-sensitive, cleavable linkers for use in cancer drug delivery systems. Kinetic analysis of eight derivatives of N-ethoxybenzylimidazoles (NEBIs) showed that their rates of hydrolysis are accelerated in mild aqueous acidic solutions compared to in solutions at normal, physiological pH. Incorporation of electron donating or electron withdrawing substituents on the phenyl ring of the NEBI resulted in the ability to tune the rates of hydrolysis under mild acidic conditions with half-lives ranging from minutes to months. A derivative of NEBI carrying doxorubicin, a widely used anticancer agent, also showed an increased rate of hydrolysis under mild acid compared to that at normal physiological pH. The doxorubicin analogue resulting from hydrolysis from the NEBI exhibited good cytotoxic activity when exposed to human ovarian cancer cells. These results demonstrate a potentially useful, general strategy for conjugating a wide range of drugs to imidazole-containing delivery vessels via NEBI functionalities for controlled release of therapeutics for drug delivery applications.     

Influence of salts on electrostatic interactions between poliovirus and membrane filters.

Neither solutions of salts nor solutions of detergents or of an alcohol at pH 4 are capable of eluting poliovirus adsorbed to membrane filters. However, solutions containing both a salt, such as magnesium chloride or sodium chloride, and a detergent or alcohol at pH 4 were capable of eluting adsorbed virus. The ability of ions to promote elution of virus at low pH in the presence of detergent or alcohol was dependent on the size of the ions and the ionic strength of the medium. These results suggest that both electrostatic and hydrophobic interactions are important in maintaining virus adsorption to membrane filters. Hydrophobic interactions can be disrupted by detergents or alcohols. It appears that electrostatic interactions can be disrupted by raising the pH of a solution or by adding certain salts. Disruption of either electrostatic or hydrophobic interactions alone does not permit efficient elution of the adsorbed virus at low pHs. However, when both interactions are disrupted, most of the poliovirus adsorbed to membrane filters is eluted, even at pH 4.     

Influence of salts on electrostatic interactions between poliovirus and membrane filters

Neither solutions of salts nor solutions of detergents or of an alcohol at pH 4 are capable of eluting poliovirus adsorbed to membrane filters. However, solutions containing both a salt, such as magnesium chloride or sodium chloride, and a detergent or alcohol at pH 4 were capable of eluting adsorbed virus. The ability of ions to promote elution of virus at low pH in the presence of detergent or alcohol was dependent on the size of the ions and the ionic strength of the medium. These results suggest that both electrostatic and hydrophobic interactions are important in maintaining virus adsorption to membrane filters. Hydrophobic interactions can be disrupted by detergents or alcohols. It appears that electrostatic interactions can be disrupted by raising the pH of a solution or by adding certain salts. Disruption of either electrostatic or hydrophobic interactions alone does not permit efficient elution of the adsorbed virus at low pHs. However, when both interactions are disrupted, most of the poliovirus adsorbed to membrane filters is eluted, even at pH 4.     

THE INACTIVATION OF TRYPSIN : III. SPONTANEOUS INACTIVATION.

1. The rate of inactivation of purified trypsin solutions approximates closely that demanded by the monomolecular formula. The more carefully the solution is purified the closer the agreement with the formula. 2. The products formed by the action of trypsin on proteins renders the trypsin more stable. Gelatin and glycine have no effect. 3. The rate of inactivation of trypsin solutions containing these products does not follow the course of a monomolecular reaction but becomes progressively slower than the predicted rate. 4. The protective action of these substances is much greater if they are added all at once at the beginning of the experiment than if they are added at intervals. These observations may be quantitatively accounted for by the hypothesis that a compound is formed between trypsin and the inhibiting substance which is stable as well as inactive, and that the rate of decomposition depends on the amount of uncombined trypsin present. 5. Trypsin is most stable at a pH of 5 and is rapidly destroyed in strongly acid or alkaline solution. 6. The protective effect of the inhibiting substances is small on the acid side of pH 5, increases from pH 5 to 7, and then remains approximately constant.     

Ion interaction reagent reversed-phase high-performance liquid chromatography determination of anti-tuberculosis drugs and metabolites in biological fluids

New methods of ion interaction reagent (IIR) RP-HPLC are presented for the determination of anti-tuberculosis drugs and their metabolites, singly or in multi-component mixtures, in biological fluids. The following analytes are considered: isoniazid, ethionamide, pyrazinamide, morphazinamide, p-aminosalicylic acid, nicotinic and isonicotinic acids. Aqueous solutions of three different ion interaction reagents are alternatively or comparatively used as the mobile phases, namely: (A) 5.00 mM octylamine at pH 3.00 for o-phosphoric acid, (B) 5.00 mM octylamine at pH 8.00 for o-phosphoric acid, and (C) 5.00 mM 1,6 diaminohexane at pH 6.00 for o-phosphoric acid. The response linearity between peak area and analyte concentration is verified for all the analytes in the concentration range within the determination limits and 2.00 mg/l. Detection limits are always lower than 82 μg/l for standard solutions; in the analysis of samples of rat serum, rat plasma and human serum, the matrix effect is negligible, the detection limits are always lower than 94 μg/l and the average recovery yield is always greater than 96%.     

Correlated positions in protein evolution and engineering

Statistical analysis of a protein multiple sequence alignment can reveal groups of positions that undergo interdependent mutations throughout evolution. At these so-called correlated positions, only certain combinations of amino acids appear to be viable for maintaining proper folding, stability, catalytic activity or specificity. Therefore, it is often speculated that they could be interesting guides for semi-rational protein engineering purposes. Because they are a fingerprint from protein evolution, their analysis may provide valuable insight into a protein’s structure or function and furthermore, they may also be suitable target positions for mutagenesis. Unfortunately, little is currently known about the properties of these correlation networks and how they should be used in practice. This review summarises the recent findings, opportunities and pitfalls of the concept.